Patent GB-1119909-A (GB)
Title: Dibenzocycloheptatriene derivatives and their preparation
Inventor: FOUCHE JEAN CLEMENT LOUIS
IPC: C07C63/72
Filed: 1967-03-28
Abstract: 2 - Methyl - dibenzo[a,d] - cycloheptatriene is prepared by reaction of anhydrous hydrogen chloride with 2-methyl-11-hydroxy-dibenzo[a, d]-cycloheptadiene in refluxing ethanol.ALSO:Novel compounds of the general Formula I <FORM:1119909/C2/1> wherein one of the symbols X is H and the other is halogen or C1-C5 alkyl, alkoxy or alkylthio, R is C1-C5 alkyl and the carbon atoms of the piperazine ring are optionally substituted by one or more methyl groups and the acid addition salts and quaternary ammonium derivatives thereof are prepared by reacting an organometallic compound of the Formula II <FORM:1119909/C2/2> in which Y is Hal-Mg-(where Hal is halogen) or Li and the piperazine nucleus may be substituted by one or more methyl groups, with a mixture of 10- and 11-halogeno-dibenzo[a,d]-cycloheptatrienes of the Formula III <FORM:1119909/C2/3> the reaction being effected in the presence of hexamethylphosphotriamide when Y is Hal-Mg-, or in an inert organic solvent when Y is Li, and separating the 10- and 11-substituted compounds.  The halomagnesium derivatives II may be prepared by reacting methylmagnesium iodide with a suitable piperazine compound. The mixture of cycloheptatriene derivatives III may be prepared by hydrolysing a phthalide of general Formula XVIII <FORM:1119909/C2/4> to give a substituted benzoic acid of Formula XVII <FORM:1119909/C2/5> which is reacted with a phenylmagnesium halide to yield a phthalide of the general Formula XV <FORM:1119909/C2/6> which is reduced to yield an acid of the Formula XI <FORM:1119909/C2/7> the methyl ester of which is reduced to yield the corresponding alcohol, which is treated with a halogenating agent to give the halogen derivative and then an alkali metal cyanide to give the nitrile derivative, which is then hydrolysed to yield an acid of the Formula X <FORM:1119909/C2/8> which is cyclized to yield a ketone of general Formula IX <FORM:1119909/C2/9> which is reduced to the corresponding alcohol and then converted to the corresponding halogen derivative which is dehydrohalogenated to yield a cycloheptatriene derivative of the general Formula VI <FORM:1119909/C2/100> wherein X1 is a halogen atom or an alkyl, alkoxy or alkylthio radical as aforesaid, which is halogenated to give the dihalogen derivative of general Formula V <FORM:1119909/C2/111> which is then dehydrohalogenated to give the required mixture III. The benzoic acid intermediates of general Formula XI may be prepared by condensing a halobenzene with a compound of the Formula XX <FORM:1119909/C2/122> to yield the keto derivative of the Formula XXI <FORM:1119909/C2/133> the CO group of which is then reduced.  The ketone derivatives IX may also be prepared by hydrolysing the final products of the invention. Pharmaceutical compositions comprise, as active ingredient, a compound of the first general formula above or a non-toxic acid addition salt or quaternary ammonium derivative thereof and a pharmaceutically acceptable carrier or coating and optionally other substances such as lubricants, wetting agents, sweeteners, perfumes and preservatives.  The compositions may be in the form of tablets, pills, powders, granules, emulsions, solutions, suspensions, syrups, suppositories and elixirs and may be administered orally, rectally or parenterally.  The compositions may be used as neuroleptics and tranquillizers and have anti-histaminic, antiserotonic, antiemetic and analgesic activity.